Prostate Cancer Studies Prostate cancer (PCa) is the most common solid tumor in (humans) men and is a major cause of cancer-related morbidity and mortality, yet its etiology and molecular underpinnings are unresolved (Eeles et al., 2014). This year, more than 161,360 men will be diagnosed with PCa, and 26,730 are predicted to die of the disease (Siegel et al., 2017). Epigenome and Gene Expression Studies In collaboration with Dr. Janet Stanford from the Fred Hutchinson Cancer Research Center (FHCRC), we contributed to an understanding of the role of tumor DNA methylation as a predictor of metastatic lethal disease in men with clinically localized PCa. Our collaborative work demonstrated the existence of, and validated, eight differentially methylated CpGs that distinguish men with metastatic lethal from non-recurrent tumors (Zhao et al., 2016). In another collaborative study, analysis of epigenomic profiling of prostate tumors identified differentially methylated genes in TMPRSS2:ERG fusion positive versus fusion-negative tumors. Many top ranked genes have corresponding alterations in mRNA expression (Geybels et al., 2015). By extension, studies of DNA methylation profiling in paired prostate cancer versus adjacent benign tissue highlighted many differentially methylated CpGs, suggesting that findings such as these could contribute to an epigenetic-based diagnostic test (Geybels et al., 2015). These studies also found that smoking-associated DNA methylation changes could explain at least some of the association between smoking and adverse PCa outcomes (Shui et al., 2016). Prostate Cancer Recurrence Study Collaborative studies with the Stanford group identified an epigenetic signature of Gleason score and prostate cancer recurrence after radical prostatectomy (Geybels et al., 2016). Genome-wide DNA methylation data from The Cancer Genome Atlas were used to generate an epigenetic signature by contrasting patients with high (8-10) versus low (6) Gleason score tumors, highlighting poorer recurrence-free survival (hazard ratio per 25% increase=1.78; 95% CI 1.48, 2.16). The signature significantly improved the area under the curve (AUC) for PCa recurrence compared to clinical-pathological parameters alone, particularly among patients diagnosed with Gleason score 7 tumors (0.64 vs. 0.76, P=1.34E-4). Results were comparable for patients with Gleason 3+4 and those with 4+3 tumors. In a separate study, genome-wide gene expression levels were measured in primary tumor samples in a population-based discovery cohort and from an independent clinical validation dataset of 78 patients. Patients were followed for >/= 5 years after radical prostatectory. Twenty-three differentially expressed transcripts in patients with metastatic-lethal compared with non-recurrent PCa were validated (P < 0.05; false discovery rate < 0.20) in the independent dataset (Rubicz et al., 2017). Rare Moderately Penetrant Variant Studies In a 2016 study headed by Ostrander lab Senior Scientist Danielle Karyadi, we completed a study aimed at identifying rare susceptibility alleles of modest penetrance (Karyadi et al., 2017). We integrated whole exome sequence (WES) data for 160 cases from 75 hereditary prostate cancer (HPC) families with array-based SNP haplotypes. Multiple metrics were utilized to select the most compelling variants, which were then analyzed in a population-based, case-control study of 2,495 men. Eight of the nine variants with predicted protein consequences (nominal p < 0.05) were in genes not previously implicated in PCa susceptibility. In an independent, nested, case-control study (PLCO trial) of 7,121 men, we observed evidence for risk associated with TANGO2 p.Ser17Ter and the established HOXB13 p.G84E variant. Meta-analysis identified two additional variants with suggestive risk. We show that inheriting two of the four risk variants was associated with a statistically significant 4.25-fold increased risk of PCa (p = 0.024). The co-occurrence result was largely driven by the combination of HOXB13 and TANGO2 variants. After stratifying by aggressiveness, TANGO2 p.Ser17Ter showed independent association with aggressive disease in both case-control studies, with a stronger risk estimate for aggressive versus nonaggressive PCa. African American Studies In African American collaborative studies, we used tumor tissue from 76 African American diagnosed with prostate cancer who had radical prostatectomy as their primary treatment and profiled their DNA methylation levels on an epigenome-wide basis. Twenty-three CpGs were differentially methylated at a statistically significant level in patients with vs. without recurrence. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence, regional vs. local pathological stage, and higher vs. lower tumor aggressiveness (Rubicz et al., 2016). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness. Prostate Tumor Sequencing Study In this study, led by Ostrander lab MD/Ph.D. student Brennan Decker, we aimed to identify clinically important molecular subtypes of PCa; hence we characterized the somatic landscape of aggressive tumors using deep, whole genome sequence (Decker et al., 2016). Our initial discovery set included ten tumor/normal pairs with Gleason scores of 8-10 at diagnosis. We analyzed for all types of variants including single nucleotide variants (SNVs), indels, and structural variants (SVs) in both the germline and tumor DNA. We found that PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for more and larger deletions. Results were validated a targeted reanalysis of 150 metastatic PCa tumors (Robinson et al., 2015), of which 18 were BRCA2 carriers, with half carrying two somatic variants and the remainder carrying one germline and one somatic variant. All BRCA2 tumors carried the same mutation signature previously observed. Future tests should be designed to leverage BRCA2 status as a biomarker and may ultimately reveal additional mutation drivers that are of importance in choosing effective therapies (Decker et al., 2016). Consortia We remain active in several prostate cancer consortia. The International Consortium of Prostate Cancer Genetics (ICPCG) played major roles in developing new statistical approaches (Larson et al., 2016; Larson et al., 2017) and construction of haplotypes across PCa risk loci, particularly on 8q (Teerlink et al., 2016). Future Aims Our future aims are to continue studies aimed at finding low frequency/moderately penetrant variants. We are also interested in testing if the mutational fingerprint we observe in BRCA2 mutational tumors extends to other DNA repair proteins and if it has prognostic value for treatment response.